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New Drug Combo Shows Promise for Treatment of Depression and Addiction
The combination of naltrexone and ketamine can help treat both symptoms of addiction and depression, a preliminary study by Yale University researchers suggests.
Substance abuse and depression are common in many patients, and efforts to treat both conditions simultaneously have had limited success. One recent study suggested that the antidepressant effects of ketamine might blunted by administration of naltrexone, used to limit cravings of those addicted to opioid drugs and alcohol.
A preliminary study of five patients suffering from both depression and substance abuse disorders suggest that isn’t the case. The study was published Jan. 9 in the journal JAMA Psychiatry.
The results “raise the possibility that for people who have depression complicated by substance abuse disorders, the combination of ketamine and naltrexone may be a strategy to explore in the effort to optimally treat both conditions,” said senior author John Krystal, Yale’s Robert L. McNeil Jr. Professor of Translational Research; professor of psychiatry, neuroscience, and psychology; and chair of the Department of Psychiatry.
Krystal and lead author Gihyun Yoon, assistant professor of psychiatry, treated the five patients suffering from depression and alcohol use disorder with a long-lasting form of naltrexone and then administered ketamine. Four of the five responded to the first ketamine dose and all five found relief from depression after multiple doses.
The study also challenges the idea that ketamine might produce antidepressant effects by stimulating opiate receptors.
Krystal cautioned that larger studies are needed to confirm beneficial effects of the combination treatment.
Krystal and Yoon have provisional patents on the use of ketamine and naltrexone to treat comorbid depression and substance abuse.
The study was primarily funded by the U.S. Department of Veterans Affairs.
Publication: Gihyun Yoon, et al., “Association of Combined Naltrexone and Ketamine With Depressive Symptoms in a Case series of Patients With Depression and Alcohol Use Disorder,” JAMA Psychiatry, 2019; doi:10.1001/jamapsychiatry.2018.3990
At NOVA Health Recovery, we do use Ketamine and other combinations to treat Alcoholism and Opioid and Pain pill addiction using Ketamine Treatment. Dr. Sendi is Board Certified in Addiction Medicine. Call 703-844-0184 Today. Fairfax, Va 22304.
Depression is a highly prevalent and very disabling condition
Global estimates are that about 350 million people worldwide are affected
Throughout North America and many other parts of the world, depression is the leading cause of disability, particularly amongst younger adults
Guidelines recommend that the antidepressants should be used as evidence-based treatments, particularly for patients with moderate-to-severe levels of depressive symptom severity
Unfortunately, less than a third of patients will achieve full remission of depressive symptoms after the first antidepressant treatment trial
What Is Pharmacogenomics/Pharmacogenetics (PGx)?
Pharmacogenomics/pharmacogenetics is the application of genetic testing to determine the effect of the body on a drug or how a drug is handled by the body (eg, distribution, metabolism) — pharmacokinetics, and the drug’s effect on the body (eg, enzymes, receptor activity) — pharmacodynamics
With pharmacogenetic testing, various genes that code for the proteins that process the drugs can be examined
Dr McIntyre: The question that often comes up from colleagues: Is pharmacogenomic testing the same thing as a genome wide analysis of the patient’s entire genome?
Dr Parikh: No, genes have been found to be relevant to either pharmacodynamics or pharmacokinetics of psychiatric medication. We do not do broad-scale genomic testing, and that is quite different
Use of pharmacogenomic testing to guide therapies is being investigated for bipolar disorder, schizophrenia, and major depressive disorder
Using PGx Testing to Select MDD Treatment: Meta-Analysis of Studies
Through a meta-analysis of studies in patients with MDD, Rosenblat et al. found that the use of a treatment-guided (TGx) approach using genomic testing, often as combinatorial testing, resulted in a greater likelihood of achieving response and remission in groups of individuals
Dr McIntyre: I have conceptualized this ability to detect an improvement in response and remission more as an additional factor to consider in which treatment I am going to select or which treatment I am not going to select
GUIDED Trial of PGx Testing vs Treatment as Usual: Study Design
24-week study, >1200 patients drawn from across the United States
Randomized; the first 8 weeks were blinded
Compared individuals having access to the results of the genetic testing, ie, the clinician knew the genetic test results from outset vs the clinician not knowing
Clinical outcomes were compared at 8 weeks, when blinding was broken.
Outpatients with MDD (median age, 49 years)
Inadequate response to ≥1 psychotropic agent (mean, 3.5 prior agents)
Primary outcome: overall change in 17-item Hamilton Rating Scale for Depression (HAMD-17) score
GUIDED Trial of PGx Testing vs Treatment as Usual: Efficacy Outcomes
Primary outcomes trended positive, but no significant differences were observed at 8 weeks between arms in HAMD-17 score change from baseline
Response and remission rates at 8 weeks were significantly better in the TGx arm than in the treatment as usual (TAU) arm
Dr Parikh: Primary outcomes are by wide measure the most important outcome of any study. There are some purists who would say that if a study has a negative primary outcome, you should throw away all the rest of the data. I do not agree with that. I agree that we should pay attention to the primary outcome, but we should look at the secondary outcomes. In this study, we had a variety of secondary outcomes. Some were related to response and remission, but others were related to safety. I think patient safety has to be kept in mind, and we should look at that data as well
GUIDED Trial of PGx Testing vs Treatment as Usual: Subset Analysis
Dr Parikh: One of the first things we were able to assess was if individuals at the start of the study on medications that were predicted not to be good fits based on pharmacogenetic testing. We were able to see in this study that if patients were on the “wrong medicines” at the start, they were far more likely to have side effects. If the medications were changed so that by 8 weeks, they were on medications that were compatible with pharmacogenetic testing, there were fewer side effects, and there was more likelihood of response or remission compared to those people who continued on medicines that were still not appropriate for them based on pharmacogenomics testing
Dr Parikh: Right now, there are about 6 genes that are extremely important in pharmacokinetics, and there are about 4 or 5 pharmacodynamic genes that are extremely important, and that is going to change over time
Dr McIntyre: In select cases, what I have done is used this guided approach as it relates to a patient who may be particularly prone to side effects or a patient where there is a safety concern, particularly as it relates to bioavailability of a treatment and potential toxicity
Factors to consider include patient preference, clinician preference, efficacy, and safety
Dr McIntyre: Do you see a role for pharmacogenomics testing for guiding adjunctive therapies like atypical antipsychotics, or if that is insufficient, moving on to next steps like lithium and so on?
Dr Parikh: Certainly, because in addition to the primary effects of any 1 medication on the person, when you are using adjunctive therapies, you are talking about 2 or 3 medications. You want to be able to anticipate what are the interactions going to be, not just based on the pharmacodynamics of a single agent, but the combined effect of several medicines. It is going to become even more relevant, and of course, there are more side effects and more safety concerns when you are mixing medicines, so you probably want to be more careful
Potential for Improving Utility of PGx Testing[17-19]
Family history is most likely a probabilistic factor or additional fact to consider when evaluating patients with MDD, along with pharmacogenomics testing
The genetic structure and genetic response of a child cannot be simply linearly predicted by what has happened with his or her parents; spontaneous mutations can occur at the point of conception and we are learning that this can have an effect on health outcomes
Clinical research has shown that in people with depression who have a history of trauma, the overall response rates to antidepressants seem to be diminished when compared to people without childhood adversity
History of current and past illness is necessary in helping select antidepressant strategies
Cost Effectiveness of PGx in Psychiatric Disorders[7,20-23]
Drs McIntyre and Parikh: While there is heterogeneity in samples and methods as well as the measures for primary and secondary outcomes, a story is beginning to unfold where there may be evidence that there is cost effectiveness for pharmacogenomics testing in groups of people who are exposed to guided therapy
Consider a holistic approach that includes patient history and medical factors to determine when pharmacogenomics should be considered, which patients may benefit, and selection and interpretation of testing
There is an urgent need for better medications that work quickly for treatment of major depression and bipolar disorder. The treatment should also be tolerable and work for depressed patients who have not responded to conventional treatments, ie, who have treatment-resistant depression (TRD).
Ketamine is a medication that is used intravenously for anesthesia, but multiple controlled trials have now demonstrated a rapid antidepressant response to a single intravenous infusion of ketamine. Controlled studies of regular infusions appear promising, but the need for regular IV infusions is not something that is appealing to most patients and often results in non-compliance. And, oral ketamine is extensive broken down by the liver before it can be absorbed by the body, so oral therapy is not a viable option. Therefore, the intranasal route has been investigated.
Intranasal drug delivery offers a route to the brain that bypasses problems related to gastrointestinal absorption, first-pass metabolism, and the blood-brain barrier; and the onset of therapeutic action is rapid. Intranasal medications avoid the inconvenience and discomfort of IV therapy. Intranasal medications have been used to treat migraine, acute and chronic pain, Parkinson’s disease, cognitive disorders, autism, schizophrenia, social phobia, and depression.
In a randomized, double-blind, placebo-controlled, crossover trial conducted in 20 patients with major depression, physicians and researchers at the Icahn School of Medicine at Mount Sinai, New York, tested the safety, tolerability, and efficacy of intranasal ketamine in patients with depression who had failed at least one prior antidepressant trial. The researchers found that a single intranasal dose of ketamine (50 mg) outperformed placebo; the response rate was 44% versus 6%, respectively. Anxiety ratings also decreased significantly more with ketamine. Patients showed significant improvement in depressive symptoms at 24 hours after ketamine compared to placebo. Intranasal ketamine was well tolerated with minimal psychotomimetic or dissociative effects and was not associated with clinically significant changes in hemodynamic parameters like blood pressure.
Intranasal ketamine represents a promising advance in treatment-resistant depression (TRD) therapeutics. Most studies report a duration of response up to 7 days and remission up to 3-5 days after a single dose. “Most adverse events … subsided spontaneously by 60 to 90 minutes post dose,” said Vanina Popova, MD. In addition, “there was no pushback” to the nasal delivery system. “The route of administration was well received, and it was certainly more convenient than intravenous administration,” she said.
Intranasal ketamine is not commercially available, but the clinical use of intranasal ketamine is increasing internationally. Research has concluded that the drug formulation, the delivery device, the technique and individual patient factors play an important role in tolerability and efficacy when using intranasal ketamine for Treatment Resistant Depression.
Intranasal ketamine has been reported in studies to help depressed patients who have not responded to conventional therapy with minimal side effects. Ask our pharmacist for more information about compounded intranasal ketamine. We customize medications to meet each patient’s specific needs.
References: Depress Anxiety. 2016 Aug;33(8):698-710. Gen Hosp Psychiatry. 2015;37(2):178–184. J Clin Psychiatry. 2015 May;76(5):e628-31. Biol Psychiatry. 2014 Dec 15;76(12):970-6. American Psychiatric Association (APA) 2018. Abstracts P7-065 and P8-054, presented May 8, 2018. Psychiatry Clin Neurosci. 2018 May 10. J Clin Psychiatry. 2017 Jun;78(6):e674-e677. CNS Drugs. 2018 May 7. [Epub ahead of print] J Psychopharmacol. 2018 Apr;32(4):397-407.
Ketamine 25mg – 100 mg Nasal Spray
BACKGROUND: The N-methyl-D-aspartate glutamate receptor antagonist ketamine, delivered via an intravenous route, has shown rapid antidepressant effects in patients with treatment-resistant depression. The current study was designed to test the safety, tolerability, and efficacy of intranasal ketamine in patients with depression who had failed at least one prior antidepressant trial. METHODS: In a randomized, double-blind, crossover study, 20 patients with major depression were randomly assigned, and 18 completed 2 treatment days with intranasal ketamine hydrochloride (50 mg) or saline solution. The primary efficacy outcome measure was change in depression severity 24 hours after ketamine or placebo, measured using the Montgomery-Åsberg Depression Rating Scale. Secondary outcomes included persistence of benefit, changes in self-reports of depression, changes in anxiety, and proportion of responders. Potential psychotomimetic, dissociative, hemodynamic, and general adverse effects associated with ketamine were also measured. RESULTS: Patients showed significant improvement in depressive symptoms at 24 hours after ketamine compared to placebo (t = 4.39, p < .001; estimated mean Montgomery-Åsberg Depression Rating Scale score difference of 7.6 ± 3.7; 95% confidence interval, 3.9-11.3). Response criteria were met by 8 of 18 patients (44%) 24 hours after ketamine administration compared with 1 of 18 (6%) after placebo (p = .033). Intranasal ketamine was well tolerated with minimal psychotomimetic or dissociative effects and was not associated with clinically significant changes in hemodynamic parameters. CONCLUSIONS: This study provides the first controlled evidence for the rapid antidepressant effects of intranasal ketamine. Treatment was associated with minimal adverse effects. If replicated, these findings may lead to novel approaches to the pharmacologic treatment of patients with major depression
Ketamine is a medication that is used to induce loss of consciousness, or anesthesia. It can produce relaxation and relieve pain in humans and animals.
It is a class III scheduled drug and is approved for use in hospitals and other medical settings as an anesthetic.
However, it is also a commonly abused “recreational” drug, due to its hallucinogenic, tranquilizing and dissociative effects.
Controversy has arisen about using ketamine “off-label” to treat depression. Off-label uses of drugs are uses that are not approved by the the United States, (U.S.) Food and Drug Administration (FDA).
Ketamine is safe to use in controled, medical practice, but it has abuse potential. Used outside the approved limits, its adverse mental and physical health effects can be hazardous. Prolonged use can lead to tolerance and psychological addiction.
Fast facts on ketamine:Here are some key points about ketamine. More detail is in the main article.
Ketamine is similar in structure to phencyclidine (PCP), and it causes a trance-like state and a sense of disconnection from the environment.
It is the most widely used anesthetic in veterinary medicine and is used for some surgical procedures in humans.
It is considered a “club drug,” like ecstasy, and it has been abused as a date-rape drug.
Ketamine should only be used as prescribed by a doctor.
What is ketamine?
Ketamine can produce feelings of dissociation when used as a drug of abuse.
Ketamine belongs to a class of drugs known as dissociative anesthetics. It is also known as Ketalar, Ketanest, and Ketaset.
Other drugs in this category include the hallucinogen, phencyclidine (PCP), dextromethorphan (DXM), and nitrous oxide, or laughing gas.
These types of drugs can make a person feel detached from sensations and surroundings, as if they are floating outside their body.
Ketamine is most often used in veterinary medicine. In humans, it can induce and maintain general anesthesia before, during, and after surgery.
For medical purposes, ketamine is either injected into a muscle or given through an intravenous (IV) line.
It is considered safe as an anesthetic, because it does not reduce blood pressure or lower the breathing rate.
The fact that it does not need an electricity supply, oxygen, or highly trained staff makes it a suitable option in less wealthy countries and in disaster zones.
In human medical practice, it is used in procedures such as:
diagnostic procedures on the eye, ear, nose, and throat
minor surgical interventions, such as dental extractions
It has been used in a hospital setting to control seizures in patients with status epilepticus (SE), a type of epilepsy that can lead to brain damage and death. However, researchers point out that ketamine is normally used for this purpose after 5 to 6 other options have proven ineffective. Ketamine for the treatment of refractory status epilepticus
It is also an analgesic, and, in lower doses, it can relieve pain.
Researchers are looking into other possible medical uses of ketamine, particularly in the areas of treatment-resistant depression, suicide prevention, and substance use disorders. However, this use is controversial.
Researchers for the American Psychological Association (APA) noted in April 2017 that a number of doctors prescribe ketamine “off-label,” for people with treatment-resistant depression.
However, they caution:
“While ketamine may be beneficial to some patients with mood disorders, it is important to consider the limitations of the available data and the potential risk associated with the drug when considering the treatment option.”
The FDA has not yet approved it for treating depression.
In a study published in BMC Medical Ethics, researchers urge doctors to “minimize the risk to patients” by considering carefully the evidence before prescribing ketamine off-label for patients to treat depression and prevent suicide.
Citing “questionable practice” regarding the prescription of ketamine, they point out that there is not enough evidence to prove that ketamine is safe, and that some studies supporting its use have not been sufficiently rigorous in terms of research ethics.
They call for open debate, more research, and for doctors to try all other options first, before prescribing ketamine.
The National Institutes of Health (NIH) are currently supporting research into whether ketamine may help people with treatment-resistant depression.
Ketamine use can have a wide variety of adverse effects, including:
changes in perceptions of color or sound
hallucinations, confusion, and delirium
dissociation from body or identity
difficulty thinking or learning
dilated pupils and changes in eyesight
inability to control eye movements
involuntary muscle movements and muscle stiffness
slow heart beat
increased pressure in the eyes and brain
It can also lead to a loss of appetite, upset stomach, and vomiting.
When used as an anesthetic in humans, doctors combine it with another drug to prevent hallucinations.
Ketamine is considered relatively safe in medical settings, because it does not affect the protective airway reflexes, and it does not depress the circulatory system, as other anesthetic medications do.
However, some patients have reported disturbing sensations when awakening from ketamine anesthesia.
Ketamine can cause an increase in blood pressure and intracranial pressure, or pressure in the brain.
People with the following conditions cannot receive ketamine for medical purposes:
brain lesion or tumor
It is used with caution in those with:
coronary artery disease
increased blood pressure
chronic alcohol addiction
acute alcohol intoxication
These effects may be stronger in people aged over 65 years.
Some people may have an allergy to the ingredients. Patients with any type of allergy should tell their doctor before using any medication.
Anyone who is using this drug for therapeutic purposes on a regular basis should have regular blood pressure checks.
As a drug of abuse
Ketamine is most often used in the dance club setting as a party drug. It produces an abrupt high that lasts for about an hour. Users report euphoria, along with feelings of floating and other “out of body” sensations. Hallucinations, similar to those experienced with LSD, are common.
In 2014, 1.4 percent of 12th graders reported using ketamine for recreational purposes. This was down from 2002, when 2.6 percent reported using it.
Street names include:
The horse tranquilizer
It is taken orally as a pill, snorted, smoked with tobacco or marijuana, or mixed into drinks. Most often, it is cooked into a white powder for snorting. Taken orally, it can cause severe nausea and vomiting.
Regardless of how it is ingested, its effects begin within a few minutes and last for less than an hour.
Higher doses can produce more intense effects known as being in the “K-hole,” where users become unable to move or communicate and feel very far away from their body.
Some users seek out this type of transcendental experience, while others find it terrifying and consider it an adverse effect.
As the user can become oblivious to their environment, ketamine abuse puts the person at risk of accidental injury to themselves and vulnerable to assault by others.
Problems with co-ordination, judgment, and the physical senses can continue for up to 24 hours. If an individual is using ketamine in a recreational setting, a sober friend should remain with them to ensure their safety.
Long-term effects include bladder and kidney problems, stomach pain, and memory loss.
If addiction and dependence develop, there is also a risk of depression.
Frequent, illegal use of ketamine can lead to serious mental disorders and major physical harm to the bladder, known as ketamine-induced ulcerative cystitis.
Ketamine and alcohol
Ketamine toxicity alone is unlikely to lead to death, according to the WHO. However, combining it with other substances, such as alcohol, can increase the sedative effects, possibly leading to a fatal overdose.
In the U.S., 1,550 emergency department (ED) visits were due to illegal ketamine use, and 71.5 percent of these also involved alcohol.
The risk of overdose is high, because, for a recreational user, there is only a slight difference in dosage between obtaining the drug’s desired effects and an overdose.
Ketamine is a Class III controlled substance. Prolonged use can cause dependence, tolerance, and withdrawal symptoms. Quitting can lead to depression, anxiety, insomnia, and flashbacks.
Chronic users have been known to “binge” their ketamine use in an attempt to experience again the dissociative, euphoric effects of their early first use.
The complications of long-term use can be fatal.
A final word
Ketamine is an anesthetic drug, used in human and veterinary medicine. It is important to distinguish the valid medical uses from the non-medical, recreational use of the drug.
When properly administered by a trained medical professional, ketamine is a safe and valuable medication.
Used in recreational settings, however, ketamine abuse can produce unpredictable physical and mental health results. In the long term, it can lead to psychological damage and, in some cases, death.
Any drug use should be prescribed by a doctor who knows the patient’s full medical history.
At NOVA Health recovery [703-844-0184 | Fairfax, Va 22306 ] we offer our patients cutting-edge treatment options for their depression, and one of our main stars is IV (intravenous) ketamine. But why does it have to be IV? “I don’t like needles, why can’t I just take this as a pill or as that nasal spray everyone is talking about?” you may be thinking. IV is the best route for your brain to receive ketamine because of something called bioavailability. In addition, it is also more effective, more precise, and safer for you.
What is bioavailability? It is the amount of medication that your body and brain is actually able to use, which is sometimes different than the amount of medication that your body receives. When you take any medication, parts of the active ingredients in them don’t go to your bloodstream; they get digested, altered into an unusable form, metabolized and excreted into your body. This is particularly prevalent in oral and intranasal medications. In fact, receiving a medication intravenously is the only way to have 100% bioavailability. Let’s take a look at the different bioavailability percentages based on what route you receive ketamine:
When we give ketamine intravenously, we know exactly where your entire dose is going: straight to your brain. The same cannot be said for other forms of ketamine. Intranasal ketamine has to bypass several layers of tissue before it can reach your brain, and too many things can happen that could cause you to lose some or most of your dose: sneezing, dripping, running down the back of your throat, etc. The same can be said for an oral pill and an intramuscular injection; these routes are just too unpredictable, and when it comes to treating your depression, we don’t want the results to be unpredictable.
When you receive IV ketamine in our office setting, it is given slowly over one hour. By doing this, we are able to monitor you closely, and if you experience any unpleasant side effects and want to stop the infusion, we are able to do that. By contrast, a dose of ketamine via intranasal spray would be done at home with no physician or nursing supervision, so side effects cannot be immediately addressed if they arise. The same is true for intramuscular or oral dosing – after you take the pill, or receive a shot of ketamine into your muscle, there is no way to stop the absorption of the medication into your bloodstream as the full dose is administered within seconds.
IV ketamine is by far the safest and most effective approach in using ketamine to treat depression. You are in a comfortable setting with healthcare providers with you the whole time, the potential for side effects is low, and you are certain that the dose you receive is the dose that is going to your brain, maximizing the benefits of this cutting-edge treatment.
However, we do offer the other routes of administration and take – home prescriptions for Ketamine therapies for those who are in our program. Contact us today at 703-844-0184 to get started on your treatment.
703-844-0184 | Alexandria, Va 22306 | Ketamine Treatment | Call for an infusion | Ketamine for depression, pain, OCD, anxiety
Ketamine for Delirium Tremens
This study suggests that ketamine can safely be used to avoid intubation and may decrease length of intensive care unit stay.
Severe alcohol withdrawal, or delirium tremens (DT), is a life-threatening condition that can require massive doses of benzodiazepines or barbiturates (GABA agonists), which can require intubation and prolonged intensive care unit (ICU) care. These authors studied a retrospective sample of adult patients admitted to a single ICU with DT to determine whether adjunctive therapy with ketamine improved outcomes.
They compared outcomes in 29 patients who received symptom-triggered therapy with GABA agonists with outcomes in 34 patients who were treated after initiation of a guideline that added an intravenous ketamine infusion (0.15–0.3 mg/kg/hour) to GABA agonist therapy. Using multivariable modeling that accounted for initial ethanol level and the total amount of GABA agonist required for treatment, patients who received ketamine had significantly lower rates of intubation (29% vs. 76% for patients who did not receive ketamine) and shorter ICU stay (5.7 days vs. 11.2 for patients who did not receive ketamine). There were no reported adverse events.
Ketamine offers a new option for people with stubborn depression that doesn’t respond to other medications.
Many people know of ketamine as a hallucinogenic and addictive street drug, which, when abused, can put people in medical peril. But today, doctors are increasingly looking to ketamine as a potentially lifesaving treatment for people with severe, treatment-resistant depression, who may be at high risk for suicide.
“Ketamine has been shown to be effective in people who have not responded to antidepressant treatment,” says Dr. Cristina Cusin, an assistant professor of psychiatry at Harvard Medical School. The fast-acting treatment has shown promise — sometimes improving depressive symptoms within hours of the first intravenous treatment.
While ketamine can offer hope to some, it’s not for everyone. The use of ketamine to treat depression is still controversial in some circles. “Some prescribers would never consider the use of a controlled substance for this purpose, because of the potential for abuse,” says Dr. Cusin. “But as with opiates, a drug is not good or bad, per se.” Still, ketamine does need to be carefully matched to the right patient for the right use to avoid harm, and treatment should be closely monitored over time.
A variety of uses
The use of ketamine in medicine isn’t new. It’s routinely used in hospitals both for anesthesia and for pain relief.
Currently, the use of ketamine for depression is “off label.” This means that although ketamine is approved by the FDA for some medical purposes, it’s not approved specifically to treat depression. However, that may soon change. Under its “fast track” drug approval process, the FDA is reviewing the results of clinical trials of esketamine, a ketamine-based nasal spray, to treat depression, says Dr. Cusin.
For now, people who undergo ketamine treatment for depression typically receive the drug at specialized clinics, either intravenously or as a nasal spray. Effects from the nasal spray last for a single day or a few days, while the intravenous treatment may last for a few weeks to a month. In both instances the dose is significantly lower than would be used for anesthesia or when used illicitly.
How ketamine works
Studies have shown that ketamine is effective in treating people whose depression has not responded to other interventions, says Dr. Cusin. Such treatment-resistant depression is estimated to affect from 10% to 30% of people diagnosed with the condition.
Experts believe that ketamine works through a unique mechanism, directly modulating the activity of a brain chemical called glutamate. Glutamate is believed to play a role in stimulating the growth of new brain connections that may help alleviate depressive symptoms.
People who have taken ketamine to treat their depression experience varying success, depending on their personal history—how long they’ve been depressed, how severe their symptoms are, and how many drugs they’ve tried without seeing improvement, says Dr. Cusin.
For people with less severe depression, ketamine may be effective in as many as 60% of those who try it. Among those with more persistent and significant disease, a smaller number, 30% to 40%, may experience relief, says Dr. Cusin. “The expectation should not be that it will magically cure depression in everybody,” she says. “Ketamine is not a perfect fix. It’s like any other medication.” In other words, it works for some people, and it won’t work for others.
To be effective, treatment with ketamine must typically continue indefinitely and involve careful monitoring. Clinicians who prescribe ketamine for depression should screen patients carefully to ensure the drug is appropriate for the individual, says Dr. Cusin. “Not everybody who wishes to try ketamine will be a good candidate,” she says.
Among those who should not use ketamine are people with
a history of substance abuse
a history of psychosis
elevated blood pressure
an uncontrolled medical condition.
Who can benefit?
Because ketamine is a newer treatment, there are still a lot of questions surrounding its use, says Dr. Cusin. For instance:
Which people respond best to treatment?
How much should be given, and how often?
What are the long-term effects of treatment?
Because the medication is being used off label for depression, there are no clearly defined safety recommendations either for home use or for its use in specialized clinics, she says. This means that it’s up to individual providers to guide the patient in making informed decisions about treatment. Choosing a qualified provider is essential. JAMA Psychiatrypublished a statement in 2017 outlining best practices for doctors to follow in ketamine treatment, such as performing a comprehensive assessment, obtaining informed consent, and documenting the severity of depression before starting the medication. These guidelines are aimed at increasing the safe use of ketamine for depression, and providers can use them to help ensure that the treatment is a good match for your condition.
As with any other medical intervention, anyone considering ketamine should also consider the drawbacks of treatment along with the potential benefits. Ketamine’s drawbacks include these:
Cost. It’s expensive and not covered by insurance. “The cost ranges from $400 to $1,200 per dose for the intravenous drug, and you may need as many as 12 to 18 doses a year,” says Dr. Cusin.
Unknowns. Ketamine hasn’t been used to treat depression for long enough for doctors to know whether there are any harmful long-term consequences of taking the medication. More time and study are needed to truly understand how it affects people over the long term.
Treatment failure. Many people with treatment-resistant depression view ketamine treatment as their last option, so if this therapy fails to improve their depression, they can be emotionally devastated. Realistic expectations and follow-up support are essential.
Even if ketamine does produce results, it’s still important to understand what it can and can’t do. “-Ketamine isn’t going to eliminate all frustrations and stress from your life. While it may lift some symptoms of depression, the life stressors will still be there,” says Dr. Cusin. You’ll still need support to help you manage them.
Side effects. While ketamine is viewed as safe in a controlled setting, it can frequently increase blood pressure or produce psychotic-like behavior, which may result in delusions or hallucinations. Serious adverse events are rare because the drug is used at such low doses, says Dr. Cusin.
However, provided you are an appropriate candidate for the treatment and your doctor monitors you closely, you could find that it improves your mood. “Ketamine could make a huge difference in the quality and duration of life and can be very effective for people who are thinking about suicide,” says Dr. Cusin.
Ketamine is emerging as a popular treatment for depression. New research suggests the drug acts like an opioid
Ketamine is emerging as a way to treat depression, but it appears to act like an opioid, Stanford researchers found.
Clinics are cropping up around the country where people receive ketamine infusions.
A handful of pharmaceutical companies, including Johnson & Johnson and Allergan, are using ketamine as inspiration for new prescription drugs to treat depression.
This is a vial of the animal tranquilizing drug ketamine hydrochloride, better known in the drug culture as “Special K.”
Ketamine is emerging as a way to treat depression, but it appears to act like an opioid — and it may carry similar risks, Stanford researchers found.
Clinics are cropping up around the country where people receive ketamine infusions. A handful of pharmaceutical companies are using ketamine as inspiration for new prescription drugs to treat depression. Yet the new research questions whether scientists know enough about chronic ketamine use to introduce it broadly.
The drug blocks NMDA receptors, which scientists think may treat depressive symptoms. Researchers wanted to test whether it was possible to elicit this reaction without activating the brain’s opioid receptors.
To block an opioid response, they gave participants naltrexone then infused them with ketamine. To compare that response with the normal response, they also gave participants a placebo before giving them the treatment.
Naltrexone so successfully blocked the anti-depressant effects of ketamine that researchers cancelled the study after the first interval because they felt it wasn’t ethical to continue it, said Dr. Nolan Williams, one of the study’s authors and a clinical assistant professor of psychiatry and behavioral sciences at Stanford University.
When patients took naltrexone, the opioid blocker, their symptoms did not improve, suggesting ketamine must first activate opioid receptors in order to treat depression, according to the study, published Wednesday in the American Journal of Psychiatry.
That’s not to say ketamine cannot be used occasionally, but it does raise questions about using it repeatedly over time, said Dr. Alan F. Schatzberg, co-author of the study and Stanford’s Kenneth T. Norris, Jr., professor of psychiatry and behavioral sciences. He likens it to opioid painkillers being an appropriate pain treatment when used once in the emergency room but posing problems, such as the risk of dependence, when used chronically.
“More studies need to be done to fully understand ketamine before it’s widely rolled out for long-term chronic use,” Schatzberg said.
Researchers planned on studying 30 adults but stopped enrolling patients once they decided combining ketamine and naltrexone was not only ineffective but also “noxious” for many participants. They tested a total of 12 people with both naltrexone and the placebo.
Of those 12, seven who received naltrexone experienced nausea after the ketamine infusion, compared to three in the placebo group. Two participants in each group also experienced vomiting.
Participants who received the placebo and ketamine treatment reported reduced depression symptoms. But those same participants did not see a decrease in depression symptoms after receiving ketamine and opioid-blocker naltrexone.
“We essentially blocked the mechanism for producing the anti-depressant effect, which were opioids,” said Williams.
The findings may have implications for clinics offering ketamine infusions and drug manufacturers trying to commercialize ketamine-like drugs.
Ketamine is meant to be used as an anesthetic. Since ketamine is currently not indicated to treat depression, insurance typically doesn’t cover the cost of infusions, so people tend to pay out of their own pocket. One session can run more than $500.
Meanwhile, drug giant Johnson & Johnson plans to seek approval from the Food and Drug Administration for its nasal spray esketamine this year after reporting positive results from a Phase 3 trial. Allergan plans to file its drug Rapastinel, which targets the NMDA receptors like ketamine, within the next two years. VistaGen Therapeutics is working on a similar drug.
In a statement, J&J said while the study reviewed ketamine and not esketamine, the findings “are difficult to interpret because of the study’s design.”
Lauren Pestikas sits as she receives an infusion of the drug ketamine during a 45-minute session at an outpatient clinic in Chicago on July 25, 2018. Pestikas struggled with depression and anxiety and made several suicide attempts before starting ketamine treatments earlier in the year. (AP Photo/Teresa Crawford)
CHICAGO (AP) — It was launched decades ago as an anesthetic for animals and people, became a potent battlefield pain reliever in Vietnam and morphed into the trippy club drug Special K.
Now the chameleon drug ketamine is finding new life as an unapproved treatment for depression and suicidal behavior. Clinics have opened around the United States promising instant relief with their “unique” doses of ketamine in IVs, sprays or pills. And desperate patients are shelling out thousands of dollars for treatment often not covered by health insurance, with scant evidence on long-term benefits and risks.
Chicago preschool teacher Lauren Pestikas long struggled with depression and anxiety and made several suicide attempts before trying ketamine earlier this year.
The price tag so far is about $3,000, but “it’s worth every dime and penny,” said the 36-year-old.
Pestikas said she feels much better for a few weeks after each treatment, but the effects wear off and she scrambles to find a way to pay for another one.
For now, ketamine has not received approval from the U.S. Food and Drug Administration for treating depression, though doctors can use it for that purpose.
Some studies show ketamine can provide relief within hours for tough-to-treat depression and suicidal behavior and clinics promising unproven benefits have popped up nationwide. But more research is needed to know long-term benefits and risks. (Oct. 31)
Ketamine has been around since the 1960s and is widely used as an anesthesia drug during surgery because it doesn’t suppress breathing. Compared to opioids such as morphine, ketamine isn’t as addictive and doesn’t cause breathing problems. And some studies have shown that ketamine can ease symptoms within hours for the toughest cases.
Its potential effects on depression were discovered in animal experiments in the late 1980s and early 1990s showing that glutamate, a brain chemical messenger, might play a role in depression, and that drugs including ketamine that target the glutamate pathway might work as antidepressants.
Conventional antidepressants like Prozac target serotonin, a different chemical messenger, and typically take weeks to months to kick in — a lag that can cause severely depressed patients to sink deeper into despair.
A vial of ketamine, which is normally stored in a locked cabinet, on display in Chicago on July 25, 2018. AP Photo/Teresa Crawford)
Ketamine’s potential for almost immediate if temporary relief is what makes it so exciting, said Dr. Jennifer Vande Voort, a Mayo Clinic psychiatrist who has used ketamine to treat depression patients since February.
“We don’t have a lot of things that provide that kind of effect. What I worry about is that it gets so hyped up,” she said.
The strongest studies suggest it’s most useful and generally safe in providing short-term help for patients who have not benefited from antidepressants. That amounts to about one-third of the roughly 300 million people with depression worldwide.
“It truly has revolutionized the field,” changing scientists’ views on how depression affects the brain and showing that rapid relief is possible, said Yale University psychiatrist Dr. Gerard Sanacora, who has done research for or consulted with companies seeking to develop ketamine-based drugs.
But to become standard depression treatment, he said, much more needs to be known.
Last year, Sanacora co-authored an American Psychiatric Association task force review of ketamine treatment for mood disorders that noted the benefits but said “major gaps” remain in knowledge about long-term effectiveness and safety. Most studies have been small, done in research settings and not in the real world.
When delivered through an IV, ketamine can cause a rapid increase in heart rate and blood pressure that could be dangerous for some patients. Ketamine also can cause hallucinations that some patients find scary.
“There are some very real concerns,” Sanacora said. “We do know this drug can be abused, so we have to be very careful about how this is developed.”
Dr. Rahul Khare, an emergency medicine specialist in Chicago, first learned about ketamine’s other potential benefits a decade ago from a depressed and anxious patient he was preparing to sedate to fix a repeat dislocated shoulder.
“He said, ‘Doc, give me what I got last time. For about three weeks after I got it I felt so much better,’” Khare recalled.
Khare became intrigued and earlier this year began offering ketamine for severe depression at an outpatient clinic he opened a few years ago. He also joined the American Society for Ketamine Physicians, formed a year ago representing about 140 U.S. doctors, nurses, psychologists and others using ketamine for depression or other nonapproved uses.
Dr. Rahul Khare poses for a portrait at his outpatient Chicago clinic on July 25, 2018. (AP Photo/Teresa Crawford)
There are about 150 U.S. ketamine clinics, compared with about 20 three years ago, said society co-founder Dr. Megan Oxley.
Khare said the burgeoning field “is like a new frontier” where doctors gather at meetings and compare notes. He has treated about 50 patients with depression including Pestikas. They’re typically desperate for relief after failing to respond to other antidepressants. Some have lost jobs and relationships because of severe depression, and most find that ketamine allows them to function, Khare said.
Typical treatment at his clinic involves six 45-minute sessions over about two weeks, costing $550 each. Some insurers will pay about half of that, covering Khare’s office visit cost. Patients can receive “booster” treatments. They must sign a four-page consent form that says benefits may not be long-lasting, lists potential side effects, and in bold letters states that the treatment is not government-approved.
At a recent session, Pestikas’s seventh, she leaned back on a reclining white examining-room chair as a nurse hooked her up to a heart and blood pressure monitor. She grimaced as a needle was slipped into the top of her left palm. Khare reached up with a syringe to inject a small dose of ketamine into an IV bag hanging above the chair, then dimmed the lights, pulled the window curtains and asked if she had questions and was feeling OK.
“No questions, just grateful,” Pestikas replied, smiling.
Pestikas listened to music on her iPhone and watched psychedelic videos. She said it was like “a controlled acid trip” with pleasant hallucinations. The trip ends soon after the IV is removed, but Pestikas said she feels calm and relaxed the rest of the day, and that the mood boost can last weeks.
Studies suggest that a single IV dose of ketamine far smaller than used for sedation or partying can help many patients gain relief within about four hours and lasting nearly a week or so.
Exactly how ketamine works is unclear, but one idea is that by elevating glutamate levels, ketamine helps nerve cells re-establish connections that were disabled by depression, said ketamine expert Dr. Carlos Zarate, chief of experimental therapies at the National Institute of Mental Health.
A small Stanford University study published in August suggested that ketamine may help relieve depression by activating the brain’s opioid receptors.
Janssen Pharmaceuticals and Allergan are among drug companies developing ketamine-like drugs for depression. Janssen leads the effort with its nasal spray esketamine. The company filed a new drug application in September.
Meanwhile, dozens of studies are underway seeking to answer some of the unknowns about ketamine including whether repeat IV treatments work better for depression and if there’s a way to zero in on which patients are most likely to benefit.
Until there are answers, Zarate of the mental health institute said ketamine should be a last-resort treatment for depression after other methods have failed.
What comes to mind when you think of Ketamine? A drug of abuse? A horse tranquiliser? An anaesthetic agent? In reality it is all three. It usually has short-term hallucinogenic effects or causes a dissociative feeling (e.g. detachment from reality, sedation, or inability to move). However, with frequent use over time it can cause permanent problems such as ‘ketamine bladder’, resulting in pain and difficulty passing urine.
What we already know
Ketamine’s effects are mainly mediated via NMDA (N-methyl-D-aspartate) receptor antagonism, although it is also an agonist at some opioid receptors and interacts with various other receptors, including noradrenaline, serotonin and muscarinic cholinergic receptors.
It is a class B illicit substance and was, in fact, upgraded from class C in June 2014 following a review of its harmful effects. Ketamine (either intramuscularly or intravenously) is licensed for use as an anaesthetic agent in children, young people and adults, but over the last few years interest has been growing in the role of Ketamine as an antidepressant agent. It is not currently licensed for this purpose.
Areas of uncertainty
A study published in 2013 suggested that a single injected dose of Ketamine was associated with a rapid-onset antidepressant effect in patients with treatment-resistant depression (Murrough et al). The biggest challenge in terms of research with ketamine is that it remains tricky to compare against a placebo, given the fairly obvious side effects of taking a hallucinogenic drug, but this study compared Ketamine with Midazolam and this is probably the best comparator so far.
The following year, an open label study was published, which found similar antidepressant effects but a whole host of adverse effects were identified (Diamond et al), including anxiety and panic symptoms, increased suicidal ideation, vomiting, headaches and the anticipated feelings of detachment, confusion and dissociative symptoms.
Ketamine remains one of the most promising new treatments for depression, both unipolar and bipolar, but it is not without its problems. Requiring specialist referral and a stay in hospital overnight for a single dose clearly has financial and logistical implications far beyond those of antidepressant tablets with a stronger evidence base behind them. We also need more information about safety and adverse effects, before it can be introduced to a wider market.
Coyle, C. M. and Laws, K. R. (2015), The use of ketamine as an antidepressant: a systematic review and meta-analysis. Hum. Psychopharmacol Clin Exp. [Abstract]
Diamond PR, Farmery AD, Atkinson S, Haldar J, Williams N, Cowen PJ, Geddes JR and McShane R. Ketamine infusions for treatment resistant depression: a series of 28 patients treated weekly or twice weekly in an ECT clinic (PDF). J Psychopharmacol, 0269881114527361, first published on April 3, 2014. [PDF]
Murrough, J.W.; Iosifescu, D.V.; Chang, L.C.; Al Jurdi, R.K.; Green, C.E.; Perez, A.M. et al. (2013). Antidepressant efficacy of ketamine in treatment-resistant major depression; a two-site randomized controlled trial. Am J Psychiatry, 170, 1134-1142. [Abstract]
In recent times, few drugs have caused more excitement among clinical researchers than ketamine. It’s well known for its role in anaesthesia and veterinary surgery (“horse tranquilizer”), as well as its illicit use, but progress has been ongoing for about 15 years to repurpose it as an antidepressant.
As a consequence, many new studies are published every month that evaluate to what extent ketamine lives up to its promise as a new antidepressant drug (Aan Het Rot, Zarate, Charney, & Mathew, 2012). To make sense of the flood of new information, naturally intrigued mental elves clearly need researchers to provide timely updates of the current state of knowledge. To this end, Coyle and Laws (2015) have recently published an extensive systematic review and the first meta-analysis that summarises the latest, methodologically sound research.
The key questions of interest to these researchers were:
Does ketamine have an immediate effect in reducing depressive symptoms?
Are the antidepressant effects of ketamine sustained over time?
Are repeat infusions more effective in reducing depressive symptoms?
Do primary diagnosis and experimental design moderate the impact of ketamine on depressive symptoms?
Do men and women experience differences in the antidepressant effect of ketamine?
This review looked at how well the effects of ketamine are maintained over 4 hours, 24 hours, 7 days and 12-14 days.
The authors followed PRISMA guidelines and scanned all relevant medical databases for studies assessing the antidepressant potential of ketamine in patients with major depressive disorder (MDD) and bipolar disorder (BD). To evaluate possible methodological factors and design variables, the authors also specifically assessed whether studies were: repeat/single infusion, diagnosis, open-label/participant-blind infusion, pre-post/placebo-controlled design and patients’ sex.
Effect sizes were calculated either relative to placebo or relative to baseline, in case no control group was provided. To correct for bias in small studies, a Hedge’s g procedure with random effects was used. Statistical heterogeneity, publication bias and moderator variables were assessed to have an idea of other variables that might influence the reported antidepressant potential of ketamine. Statistical heterogeneity among studies was assessed using I² values, with values above 50% generally representing substantial heterogeneity.
In total, 21 studies enrolling 437 patients receiving ketamine were identified that satisfied inclusion criteria:
17 were single infusion studies and the majority reported data collected at 4h (11) and 24h (13) after ketamine treatment
6 studies had follow-up for 7 days
4 studies had follow-up for 12-14 days
In general, there are grounds to assume publication bias for single infusion studies at 4h and 24h.
Of the 21 included studies, 2 were judged to be at a high risk of bias, 13 medium risk and 6 low risk of bias.
In general, ketamine had a large statistical effect on depressive symptoms that was comparable across all time points
Effect sizes were significantly larger for repeat than single infusion at 4 h, 24 h and 7 days
For single infusion studies, effect sizes were large and significant at 4 h, 24 h and 7 days
The overall pooled effect sizes for single and repeated ketamine infusions found no difference at any time point, suggesting that the antidepressant effects of ketamine are maintained for at least 12-14 days
Moderator analyses suggest that responsiveness to ketamine may vary according to diagnosis. Specifically, while ketamine produced moderate to large effects in both MDD and BD patients, the effect of a single infusion was significantly larger in MDD than BD after 24h. On the other hand, after 7 days, this pattern reversed and ketamine showed higher efficacy in BD patients. However, the small number of studies makes it tricky to draw any conclusions.
In addition, single-infusion pre-post comparisons did not differ in effect size estimation from placebo-controlled designs except for at 12-14 days, where only one study was available. In a similar vein, there were no effect size differences between single infusion studies with open-label and blinded infusions.
Of note, the meta-analysis found the percentage of males in the group was positively associated with ketamine’s antidepressant effects after 7 days, although this finding warrants replication with more data points.
There’s plenty of room for improvement in the primary research, but this meta-analysis shows ketamine in a promising light as an antidepressant.
The authors conclude:
Single ketamine infusions elicit a significant anti-depressant effect from 4h to 7days; the small number of studies at 12-14 days post infusion failed to reach significance. Results suggest a discrepancy in peak response time depending upon primary diagnosis – 24 h for MDD and 7 days for BD. The majority of published studies have used pre-post comparison; further placebo-controlled studies would help to clarify the effect of ketamine over time.
This meta-analysis suffers from several limitations that are inherent in the available studies:
For one, there were only four studies that assessed the effect of repeated ketamine infusions, which is a shame given that maintenance of antidepressant effects is one of the key drawbacks of rapidly acting interventions
In addition, the authors note that their results suggest publication bias, which may be taken to indicate that several negative findings have not been published and thus could not be included in this meta-analysis
Also, more information about adverse effects would have been useful, especially to evaluate whether ketamine can be safely applied in a broader clinical context
This is the first meta-analysis to evaluate ketamine’s antidepressant effects. For single infusion specifically, ketamine exerts large antidepressant effects in MDD as well as BD patients that seem to last at least 7 days, while too few studies are available beyond this time point.
It’s noteworthy that the effect sizes did not differ between time points, which indicates that the effect of a single infusion remains relatively stable in the short-term. While repeated infusions were shown to provide higher effects than single infusions at least for the first week, more studies are needed to corroborate the supremacy of repeated treatment.
Before ketamine can become a clinically viable treatment option, however, this review makes it clear that more methodologically refined studies (especially RCTs with adequate placebo controls) need to be conducted. With this in mind, researchers should take these findings as an incitement to action!
High quality placebo controlled trials are needed to drive forward progress in this field.
Coyle, C. M. and Laws, K. R. (2015), The use of ketamine as an antidepressant: a systematic review and meta-analysis. Hum. Psychopharmacol Clin Exp, doi: 10.1002/hup.2475. [PubMed abstract]
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